The discovery of osteoarthritis biomarkers could speed up the process of determining a drug's effectiveness.

By Mary Anne Dunkin

Testing new treatments for osteoarthritis presents challenges unlike those of other forms of arthritis. Because OA often progresses slowly, determining a drug’s effectiveness against progression can be a drawn-out process – a process the manufacturer won’t likely repeat if the first attempt proves unsuccessful, says Virginia Byers Kraus, MD, PhD, professor of medicine at Duke University. The discovery of osteoarthritis biomarkers, however, could eventually change all of that, she says.

A biomarker is defined as a clinically-relevant physical or biological measure that can be used to evaluate disease onset, activity and progression. For OA, biomarkers could serve as a stand-ins for traditional X-rays, says Dr. Kraus, and thus hasten the discovery and evaluation of new treatments.

Currently, trials for OA treatment last anywhere from three to five years, says Dr. Kraus. “That is really long time to wait not knowing if all this time and effort by patients, researchers and the drug company are going to be paying off in dividends.”

If, after a three-to-five year trial, a therapy is shown not to work, drug companies may be hesitant to pursue development of other treatments, says Dr. Kraus. “Most companies at that point say, ‘We have invested too much time and money and now we are out of here,’ and that is not good for patients with osteoarthritis because we still don’t have anything that we know for sure will slow down progression,” she says. “We need to develop a kind of playing field that will make things possible, that will allow there to be studies done in a reasonable time with a reasonable cost without getting everybody discouraged.”

As the leader of international team of scientists studying osteoarthritis biomarkers, Dr. Kraus and her colleagues are currently looking at a dozen that could potentially be used to develop that playing field, to determine in a short period of time if arthritis is worsening, she says.

The study is supported by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, a public-private partnership that combines expertise from NIH, the FDA, academia, pharmaceutical companies, the Arthritis Foundation and other nonprofit organizations.

“The idea is that [these markers] would allow companies to do studies of therapeutic interventions and get a very early indication of whether a person’s arthritis is worsening or staying stable.”

Types of Biomarkers

Basically these biomarkers fall into three categories:

MRI markers measured on serial MRIs of the knee

X-ray markers that look at more subtle features of the knee than traditional X-rays

Biochemical markers measured in the blood and the urine

Testing new treatments for osteoarthritis presents challenges unlike those of other forms of arthritis. Because OA often progresses slowly, determining a drug’s effectiveness against progression can be a drawn-out process – a process the manufacturer won’t likely repeat if the first attempt proves unsuccessful, says Virginia Byers Kraus, MD, PhD, professor of medicine at Duke University. The discovery of osteoarthritis biomarkers, however, could eventually change all of that, she says.

A biomarker is defined as a clinically-relevant physical or biological measure that can be used to evaluate disease onset, activity and progression. For OA, biomarkers could serve as a stand-ins for traditional X-rays, says Dr. Kraus, and thus hasten the discovery and evaluation of new treatments.

Currently, trials for OA treatment last anywhere from three to five years, says Dr. Kraus. “That is really long time to wait not knowing if all this time and effort by patients, researchers and the drug company are going to be paying off in dividends.”

If, after a three-to-five year trial, a therapy is shown not to work, drug companies may be hesitant to pursue development of other treatments, says Dr. Kraus. “Most companies at that point say, ‘We have invested too much time and money and now we are out of here,’ and that is not good for patients with osteoarthritis because we still don’t have anything that we know for sure will slow down progression,” she says. “We need to develop a kind of playing field that will make things possible, that will allow there to be studies done in a reasonable time with a reasonable cost without getting everybody discouraged.”

As the leader of international team of scientists studying osteoarthritis biomarkers, Dr. Kraus and her colleagues are currently looking at a dozen that could potentially be used to develop that playing field, to determine in a short period of time if arthritis is worsening, she says.

The study is supported by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, a public-private partnership that combines expertise from NIH, the FDA, academia, pharmaceutical companies, the Arthritis Foundation and other nonprofit organizations.

“The idea is that [these markers] would allow companies to do studies of therapeutic interventions and get a very early indication of whether a person’s arthritis is worsening or staying stable.”

Types of Biomarkers

Basically these biomarkers fall into three categories:

MRI markers measured on serial MRIs of the knee

X-ray markers that look at more subtle features of the knee than traditional X-rays

Biochemical markers measured in the blood and the urine

Of these, the biggest group are the biochemical markers, says Dr. Kraus. Biochemical biomarkers being studied for osteoarthritis fall into the further categories of markers of cartilage and bone degradation and formation, and markers of inflammation.

Every tissue in the body is always undergoing breakdown and repair, explains Dr. Kraus. “We think of osteoarthritis as being an imbalance in the normal amount of breakdown and repair – where you have excessive breakdown compared to the amount of the repair.”

Products of this excessive breakdown – including fragments of joint cartilage proteins such as collagen and aggrecan – can be found in the urine and may serve as markers for active disease. Similarly, high levels of enzymes involved in joint breakdown would be indicative of inflammation and osteoarthritis in a progressive state, she says.

Comparing the Candidates with OAI Database

The researchers are looking at and comparing 12 candidate biomarkers head to head using data and samples from the Osteoarthritis Initiative (OAI)—a multi-center, prospective observational study of knee OA designed to provide a resource for researchers evaluating OA biomarkers. “We anticipate that a combination of markers from these three categories may all be used together as a panel to try to give the best indication of what the patient status and progression status is.”

A public-private partnership, the OAI established a natural history database for osteoarthritis that includes clinical evaluation data, radiological images and a biospecimen repository from 4,796 men and women between the ages of 45 and 79. Data and images collected through the seven-year project are available to researchers around the world to help speed the identification of OA biomarkers and development of agents to slow or stop OA progression.

Led by Dr. Kraus and David Hunter, MD, PhD, at the University of Sydney, Australia, scientists are now using the data to look at baseline and one- and two-year changes in these types of markers to determine if they can predict during the course of one or two years what is happening four years later. To do this, they are comparing markers of 200 people who had worsening of X-rays and symptoms, 100 who had worsening of X-rays only and 100 who had worsening of symptoms only to 200 people who have not experienced worsening.

“If these markers can predict four-year outcomes and they can do that robustly and with great assurance and are truly representative of what is happening, the hope is that down the road the FDA would eventually approve different outcomes for clinical trials,” says Dr. Kraus. “This would facilitate treatment intervention and make it possible for treatment trials to ultimately make difference in the lives of patients.”